IL-1alpha has antiproliferative activity against human melanoma cell lines, causes murine melanoma tumors to shrink in vivo, can induce interferons and interleukin-2 which have activity in melanoma, and can enhance the activity of cytotoxic T cells and other effector cells. Animal studies suggest that indomethacin increased the antitumor effects of IL-I. For these reasons, we designed this phase II study in melanoma patients to determine the anti-tumor activity of IL-1alpha plus indomethacin using the maximum tolerated dose of IL-1alpha from our earlier phase I trial. A total of 49 patient have entered the study, and all are evaluable for response. None of the 14 patients with predominately visceral metastases responded to treatment. Of the 35 patients with non-visceral metastases, four patients responded (1 CR, 3 PR) for a response rate of 11 % (95% confidence interval: 5-26%). These results indicate that IL-1alpha has a low level of activity in melanoma. In effort to enhance this activity, we amended this trial to combine etoposide (VP-16) with this regimen based on preclinical studies that demonstrated synergistic antitumor effects with the combination. Of the 23 patients enrolled to date, 20 are evaluable. Fourteen patients have had predominantly visceral metastases and six patients have had predominantly non-visceral metastases. One patient had a partial response to therapy; three patients had stable disease.